Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited disorder in humans, with a frequency in the general population of 1 in 1000 (Dalgaard, Dan, Med Bull 4:128–133 (1957)). Approximately 85% of ADPKD cases are caused by mutations in the PKD1 gene (Consortium TEPKD: The Polycystic Kidney Disease 1 Gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16, Cell 77:881–894 (1994); Consortium TIPKD: Polycystic kidney disease: the complete structure of the PKD1 gene and its protein, Cell 81:289–298 (1995)), located on human chromosome 16p13.3; the remaining 15% are caused by mutations in the PKD2 gene, located on human chromosome 4q21–23 (Kimberling et al., Genomics 18:467–472 (1993); Peters et al., Nat Genet 5:359–362 (1993)). ADPKD is characterized by the formation of fluid-filled cysts in the kidneys and the average age of onset is 40 years, with end-stage renal disease (ESRD) occurring by age 60 in 50% of cases (Gabow, N, Engl J Med 329:332–342 (1993)). PKD significantly affects quality of life for an extended period of time (Dalgaard, Dan, Med Bull 4:128–133 (1957)); it is estimated that approximately 1 in 2,000 Americans is on kidney dialysis for approximately 10–15 years of their life. Hence, a majority of PKD cases lead to costly, invasive and chronic health care. Efforts to study PKD have been hampered by the lack of a reliable model system for the disease.
Companion animal species, such as the domestic cat, are effective models for several inherited diseases and should be used to develop better drug and gene therapies for PKD. Feline PKD is an inherited disease in Persian and Persian-related cats. As with humans, PKD in cats is characterized by renal as well as hepatic and pancreatic cysts (Eaton et al., Vet Pathol 34:117–126 (1997)) and has an autosomal dominant mode of inheritance (Biller et al., J Amer Vet Med Assoc 196:1288–1290 (1990)). Approximately 37% of Persian cats in the United States (Cooper, Feline Prac 28:20–21 (2000)), and 38% worldwide (DiBartola, Proceedings of the 18th Annual Veterinary Medical Forum of the American College of Veterinary Internal Medicine Seattle, 438–440 (2000)) are PKD affected. Only 20% of the cat population in the United States is represented by purebred cats, but of purebreds, Persians and Persian-derived breeds constitute approximately 80% of the cat fancy. This implies that approximately 6% of the cat population in the United States has PKD, making it the most prominent inherited feline disease, hence PKD is the most prominent inherited feline disease. Thus, the cat is an exceptional animal model for studies of PKD. However, methods for identifying cats who are carriers for PKD prior to development of disease have been limited.
Further investigation into the cause of PKD will be valuable for feline health as well as provide insights into human ADPKD. As with humans, cats have a wide range of disease progression and severity, thus other genetic and environmental factors could influence disease progression (Bogdanova et al., Hum. Genet. 95:645–650 (1995); Parfrey et al., Kidney Int. 61:1925–1934 (2002); Tahvanainen et al., J. Hepatol. 38:39–43 (2003); Magistroni et al., J. Nephrol. 16:110–115 (2003)). Currently, the disease is highly prevalent in the cat population, making the identification of severe, early-onset cases and mild, late-onset cases feasible. This could lead to the identification of genetic modifiers of the disease. As cats have similar clinical presentations, therapies that are under development for EGFR receptors could be tested for efficacy in the cat, prior to use in humans (Magistroni et al., J. Nephrol. 16:110–115 (2003); Torres et al., Kidney Int. 64:1573–1579 (2003); Sweeney et al., Kidney Int. 64:1310–1319 (2003); Dell et al., Kidney Int. 60:1240–1248 (2001); Davis et al., Semin. Nephrol. 21:430–440 (2001); Avner et al., Int. J. Dev. Biol. 43:457–461 (1999); Sweeney et al., Kidney Int. 56:406–413 (1999); Sommardahl et al., Pediatr. Nephrol. 11:728–733 (1997); Murcia et al., Pediatr. Nephrol. 12:721–726 (1998); Bagowski et al., EMBO J. 18:5567–5576 (1999)).
It is currently recommended that Persian and Persian-related cats be screened for PKD by ultrasound before they are bred (Cannon and Barr, Vet. Rec. 147:639–640, (2000)). Knowledge of the mode of inheritance, coupled with the accuracy and availability of ultrasonography, a non-invasive technique for diagnosis, has made the elimination of feline PKD possible (Barrs et al., Austral. Vet. J. 79:257–259 (2001)). Although breeders are advised not to breed positive cats, they are often bred for several unrelated reasons; 1) clinical signs have not yet appeared, which is generally when approximately 66% of the normal kidney function has been lost, 2) many breeders are still unaware of the disease and its prevalence in their cattery, 3) ultrasound is either unavailable or cost prohibitive for generalized screening, 4) breeding decisions are made prior to adequate accuracy of diagnosis as determined by ultrasound, and 5) the disease is highly prevalent, thus many catteries could lose approximately 50% of their breeding population, causing a large loss to the gene pool. With the identification of a causative mutation, a genetic test for feline PKD will provide breeders with an efficient and accurate means by which to selectively breed their cats and remove PKD from the population. The point mutation alters a restriction enzyme site, thus typing for PKD could be efficiently performed by RFLP analysis. Additionally, various other techniques for point mutation typing such as, denaturing high performance liquid chromatography (dHPLC), single-strand conformation change polymorphisms (SSCP) and various sequencing techniques could effective identify the PKD mutation. Since PKD has been found in random bred, Siamese and other cat breeds that have relationships with Persians, it will be important to monitor the progression of the disease in these breeds as well as in Persians worldwide.
Thus, there is a need in the art for compositions and methods for detecting genes associated with PKD and for identifying carriers of polycystic kidney disease. The present invention satisfies these and other needs.